Nutritional Antioxidants

Published on 15/03/2015 by admin

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Chapter 18 Nutritional Antioxidants

Dermatologists today have the capability of preventing damage to normal skin and even retarding the skin’s natural aging through the use of cosmeceuticals. Especially during the past decade, research has demonstrated the efficacy of many topical nutrients, particularly antioxidants—some not synthesized by humans and therefore essential (vitamins C and E), some self-synthesized (α-lipoic acid, ubiquinone), and some exogenous (genistein). The challenge is to make topical formulations which attain percutaneous absorption of active forms and which maintain antioxidant activity. Such cosmeceuticals could protect as well as reduce and reverse manifestations of aging skin.


R-Alpha lipoic acid (αLA) is synthesized in the mitochondria of plants and animals, including humans. Natural αLA is covalently bound to protons via lysine; thus only minimal free αLA enters the circulation after biosynthesis or eating αLA-rich food. The lipoamide is a required cofactor for two enzymes in the citric acid cycle. It is also essential for the formation of a cofactor required in nucleic acid synthesis and for the metabolism of branched chain amino acids.

With oral supplements of free αLA, unbound αLA is transported to tissues. Free αLA is rapidly metabolized by the liver, so that the half-life in blood after absorption is only about 30 minutes, limiting the amount delivered. High tissue levels are short lived since most free αLA is rapidly reduced to dihydrolipoic acid (DHLA), as shown in Figure 18.1.

Notwithstanding this transient availability, free αLA has been shown to be therapeutic for autoimmune liver disease by binding autoantibodies, heavy metal intoxication by trapping circulating metals, diabetic polyneuropathy by preventing oxidative damage and mushroom poisoning. Although not normally found in significant amounts in the skin, αLA is a good candidate for topical application:

Indeed, αLA has been found to penetrate rapidly into murine and human skin to dermal and subcutaneous layers. Two hours after application of 5% αLA in propylene glycol, maximum levels of αLA were attained in the epidermis, dermis, and subcutaneous tissue. The stratum corneum concentration of αLA predicted the penetration and levels in the underlying skin. 5% of the αLA was converted to DHLA in both the epidermis and dermis, leading the researchers to conclude that both keratinocytes and fibroblasts reduce αLA.

Topical αLA with its metabolite DHLA could protect the skin from oxidative stress in several ways. Both αLA and DHLA are highly effective antioxidants as summarized in Table 18.1. DHLA is actually the more potent form. Both successfully scavenge reactive oxygen species (ROS) in vitro and in vivo. However, pro-oxidant activity has been observed. This occurs when an antioxidant reacts with a ROS scavenger, forming a product that is more harmful than the scavenged ROS. Fortunately, αLA can act as an antioxidant against the pro-oxidant activity of DHLA (Biewenga et al). Both αLA and DHLA further provide antioxidant activity by chelating Fe2+ and Cu2+ (αLA) and Cd2+ (DHLA).

Table 18.1 Antioxidant activity of α-lipoic acid and DHLA

  α-Lipoic acid DHLA
Antioxidant + ++
Scavenges reactive oxygen species (ROS) + +
Chelates metals:
Fe2+, Cu2+ +
Cd2+ +
Regenerates endogenous antioxidants (vitamin E, vitamin C, glutathione, ubiquinol) +
Repairs oxidatively damaged proteins +
Pro-oxidant + +

+ activity; ++ greater activity; − no activity. DHLA, dihydrolipoic acid.

Reproduced with permission from Biewenga GP, Haenen GRMM, Bast A 1997 The pharmacology of the antioxidant lipoic acid. General Pharmacology 29:315–331.

DHLA, unlike αLA, has the capacity to regenerate the endogenous antioxidants vitamin E, vitamin C, glutathione, and ubiquinol, as illustrated in Figure 18.2. This is clearly of great importance for skin, since UV exposure directly depletes ubiquinone and vitamin E in particular, as well as vitamin C, thereby stressing the other linked antioxidants. Regeneration of these major membrane and cytosol antioxidants gives cascading protection. Increases in the other important antioxidants (intracellular glutathione and extracellular cysteine) are noted when αLA is added to cell cultures. Vitamin E-deficient animals do not show symptoms (weight loss, neuromuscular abnormalities) when supplemented with αLA.

Although αLA is a potent antioxidant, it provides no effective protection against UV-induced erythema or cell damage measured as sunburn cells. However, αLA (but not DHLA) acts as an anti-inflammatory agent by reducing the production and inhibiting the binding of transcription factors such as nuclear factor kappa B (NF-κB), thereby indirectly affecting the gene expression of inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α) and interleukins. DHLA (but not αLA) can repair oxidatively damaged proteins, which in turn regulate the activity of proteinase inhibitors such as α1-AP, an inflammatory modulator. In vitro, both αLA and DHLA inhibit lipolysaccharide-induced nitric oxide (NO) and prostaglandin E2 (PGE2) formation and suppress inducible NO synthase (iNOS) but do not affect the expression of cyclooxygenase-2 (COX-2). In a mouse model, topical DHLA inhibits chemically induced activation of skin inflammation with a concomitant decrease in inflammatory modulators. Furthermore, topical DHLA (but not oral αLA) reduces chemically induced skin tumor incidence and multiplicity, and inhibits iNOS and COX-2 in a dose-dependent manner. As antioxidants, both αLA and DHLA are directly anti-inflammatory by virtue of their quenching oxidants secreted by leukocytes and macrophages at sites of inflammation.

αLA and DHLA have been shown to be effective depigmenting agents. Both depigment dark-skinned swine, inhibit tanning of light-skinned swine, and inhibit chemical and UVB-induced tyrosinase activity in melanocyte cultures. A recent new derivative of α-lipoic acid has been proven to be an effective depigmenting agent in melanoma cells in vitro. This depigmentation is achieved by formation of DAPA conjugate products.

αLA may prove to retard and correct both intrinsic and extrinsic aging of the skin as well as other organs. By damaging DNA, the ROS continuously formed in normal metabolism may be largely responsible for the functional deterioration of organs with aging. A decrease in cellular protein and DNA as well as in αLA levels has been measured in aged rat liver, kidney, and spleen. Supplementation with αLA increases nucleic acid and protein levels in the elderly organs. Similarly, the age-related decrease of mitochondrial function in cardiac and brain cells can be improved with αLA supplementation. Clearly, aging skin might similarly benefit.

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